JP3331413B2 - Artificial bone for implantation - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to an implantable artificial bone device, and more particularly to a protease formed as a composite including a bone growth inducing layer or coating.

BACKGROUND OF THE INVENTION Many bone prosthesis devices, such as those used for hip reconstruction, are provided by fitting a fixation portion into the tubular portion of the medulla or by using a bone cement such as polymethyl methacrylate. Is joined to the skeleton by mechanically securing the device. However, these methods are not fully satisfactory because the instruments tend to loosen by impact or as a result of long-term use. In attempts to secure the bone prosthesis in place, ingrowth of tissue has been used. The prosthesis of this method is provided with a porous surface to aid in the ingrowth of bone and to serve as a site for attachment of new bone tissue. The method of ingrowth of tissue to fix the prosthesis has been applied to various endoprostheses.

U.S. Pat. No. 3,986,212 describes a porous polymeric membrane for bone fixation by ingrowth of tissue. Useful porous polymeric materials are those having interconnected pores of a particular density and a particular average diameter. Among the polymeric materials described are high density polyethylene and polypropylene or mixtures thereof with certain critical parameters. The coating has also been shown to be mechanically secured or chemically bonded to the device.

Similarly, the prosthetic device of U.S. Pat. No. 4,164,794 is a porous thermoplastic material having a special property that is adapted to the ingrowth of spongy and cortical bone specules and is said to be inducible. It is covered with.

The fixed portion of the endoprosthesis device described in U.S. Pat. No. 4,202,055 has a non-porous polymer membrane to which ceramic particles have been added. Resorption of the ceramic particles creates a polymeric structure with open pores that penetrate the newly formed bone.

According to U.S. Pat. No. 4,713,076, the fixation part of a bone prosthesis has a completely resorbable membrane which allows for rapid and deep ingrowth of new bone tissue and is said to fix the implant inside the bone . The membrane composition is made of a calcium compound, such as tricalcium phosphate or apatite (hydroxyl apatite), formed in the form of highly porous spherical particles, comprising polyamino acids, polylactates,
It is embedded in a resorbable and biologically compatible binder such as polyglycolate, a co-condensate of these materials, gelatin or collagen.

Other types of coated artificial bone devices are disclosed in U.S. Patent Nos. 3,808,606; 4,159,358; 4,168,326;
35,069, 4,365,356, 4,491,987, 4,652,45
No. 9, 4,702,930 and 4,705,694.

It is also known to use milled exogenous bone growth material obtained from, for example, demineralized homogenous or heterogeneous bone. Nos. 4,485,097 and 4,678,4 U.S. Pat.
Nos. 70 and 4,743,259; Volander et al., "Use of demineralized bone matrix in the treatment of partial injury."
Journal of Bone and Joint Surgery, Vol. 68-A, No. 8, 1
264-1273; Growacky et al., "Demineralized Bone Implantation", Symposium on Horizons in Plastic Surg
ery, 12, No. 2, 233-241 (1985); Gebstein et al., "Crosslinking of large bone defects with a powdered demineralized bone matrix", The Journal of Bone and Joint Surgery, 6
9-A, No. 7, 984-991 (1987); Melonich, "Decalcified lyophilized bone allograft as an implantable material in human periodontal ligament defects" The International Journal of Peri
odontics and Restorative Dentistry, pp. 41-55 (1
984.6) and Kavan et al., "Treatment of Jaw Defects with Demineralized Bone Implantation", Journal of Oral and Maxillofa
See cial Surgery. However, the conventional description does not give any suggestion about the combination of these artificial bone components and the bone growth inducing component based on the powdered bone material.

(Solution of the Problem) An object of the present invention is to provide an artificial bone implant having a bone growth inducing component.

It is an object of the present invention to specifically elucidate the osteogenic effect of demineralized bone powder in which at least a part of the endoprosthesis surface is optionally distributed in a biocompatible and non-bioerodable binder or matrix. It is an object of the present invention to provide an endoprosthesis, such as a hip joint replacement, having a membrane or layer with the same.

For these purposes of the invention, the surface of at least a portion of the artificial bone implant has a bone powder component adhered to it. As the bone powder is gradually resorbed, new bone ingrowth is replaced by resorbed bone particles, and there is a tighter connection between the artificial bone and the existing bone tissue. Unlike non-osteogenic particles contained in known prosthetic membranes, such as those described in U.S. Pat.No. 4,202,055, demineralized bone powder applied to the endoprostheses of the present invention is endosseous. Provides a significant osteogenic effect that significantly promotes proliferation.

 The present invention will be further described based on specific embodiments.

The demineralized ground or powdered bone added to the osteogenic layer or membrane is a known type of material and is manufactured by known methods. As used herein, "crushed bone", "milled bone" and "bone powder" refer to bone particles having an average particle size from relatively fine to coarse and from larger pieces. Includes For example, the bone powder used in the present invention may be from about 0.1 to about 1.2 cm, preferably
Particles having an average diameter of 0.2 to 1 cm may be used. Bone powder can be obtained from a variety of sources, including human allografts, xenografts, and can be spongy tissue and / or cortical tissue.

In a preferred method of demineralizing bone, the bone is first ground to a desired average particle size, degreased and disinfected, and demineralized with an acid. A preferred degreasing solution is an aqueous ethanol solution. Ethanol is a good solvent for lipids and water is a good hydrophilic carrier that allows the solution to penetrate deeper into the bone. The aqueous ethanol solution kills vegetatively growing microorganisms and viruses and also disinfects bone. For optimal lipid removal and disinfection in the shortest amount of time, typically at least about 10-40% water (i.e., about 60% of a degreaser such as alcohol).
~ 90%) must be present in the degreasing solution. The preferred concentration of the degreasing solution is about 60-85% alcohol, preferably 70%. After defatting, the bones are demineralized by soaking in a pH adjusted acid such as 0.6N hydrochloric acid for about 3 hours. Other acids that can be used at the same or different concentrations include inorganic acids and organic acids such as peracetic acid. After acid treatment, the bone powder is washed with water for injection buffered with a buffer such as a 0.1 M sodium phosphate solution to finally adjust the pH and finally to remove residual hydrochloric acid and sodium phosphate. Washed with water for injection. This demineralized bone powder can be used immediately in the artificial bone device of the present invention, or before use.
It can be stored in a sterile condition, preferably in a lyophilized condition.

If necessary, the bone powder can be modified in one or more ways. For example, the porosity of the bone powder can increase it. Bone powder may also contain one or more denaturing agents, such as US Pat.
It can be treated with glutaraldehyde as described in 678,470. Among other optional treatments is a method for increasing the protein content of powdered bone using the method of US Pat. No. 4,743,259. After the bone powder is immersed in the desired substance solution, the bone particles can be dried to introduce various substances into the bone particles. Substances that can be easily added to bone particles by these methods include antiviral agents, such as those suitable for preventing acquired immunodeficiency syndrome (AIDS) transmission; erythromycin, bacitracin, neomycin, penicillin, polymyxin B,
Antibacterial and / or antibiotics such as tetracyclines, biomycin, chloromycetin and streptomycin, cefazolin, ampicillin, tobramycin, clindamycin and gentamicin; amino acids, peptides, vitamins, inorganic elements, NAD and / or other nutrition Agents; hormones; endocrine gland tissues or tissue fragments; synthesizers; enzymes such as collagenases, peptidases, oxidases; skeletons of polymer cells with parenchymal cells; angiogenic agents and polymer carriers with these agents; Compatible surfactants; antigenic formers; cytoskeletal agents; biologically active ingredients such as bone morphogenetic protein (BMPa), transforming growth factor (TCF-β), and insulin-like growth factor (IGD-1) ; Maba Ele Osteolytic agents; antitumor agents; cell attractants and adhesives; immunosuppressants; permeability enhancers, for example, fatty acid esters such as laurate, myristate, and stearate monoesters of polyethylene glycol, enamine derivatives, alpha. -Keto aldehydes and nucleic acids. The amount of material added arbitrarily can vary widely, and the optimum amount can usually be readily determined for a particular case by experiment.

The attached bone powder component of the artificial bone can be applied to the surface of the artificial device by any method. Thus, for example, the bone particles and / or the surface of the prosthesis may be coated with a suitable cement or adhesive known in the art, such as cyanoacrylate, silicone,
Using a high-temperature melting adhesive or a cellulosic binder, the bone particles are brought into contact with the prosthesis, and the bone particles are applied by spraying, coating, or the like so as to sufficiently adhere to the surface of the prosthesis or to a predetermined region or site of the surface. it can. Another convenient method is to apply a charge to the prosthesis and an opposite charge to the bone powder, i.e., attract and fix the bone powder to the surface of the prosthesis by electrostatic precipitation. Each of these applications is repeated one or more times to form a relatively thick bone powder layer on the surface of the prosthesis, for example, a powder-adhered layer 20 times or more thicker than the average diameter of the bone powder. it can.

In certain embodiments of the invention, the bone powder is applied to the prosthesis as part of a membrane or layer in which the bone particles have been incorporated into a biocompatible, non-bioerodable binder. "Non-bio-erodable" as used herein
Is easily or quickly reabsorbed (ie bioabsorbed) by the human body
It refers to a substance that is not absorbed but does not exclude it and that will be absorbed to some extent after being in the body for a long period of time, for example, two years. Convenient biocompatible, non-bioerodable materials that can be used in the manufacture of prosthetic membranes or layers include enamels or enamel analogs, such as U.S. Patent Nos. 4,168,326 and 4,365,356, the contents of which are incorporated herein by reference. Inorganic materials and porous high-density polyethylene, polypropylene, polysulfone, polyphenylene sulfide, polyacetal, thermoplastic polyester, polyamide, polyamideimide, thermoplastic polyimide, polyaryletherketone, polyarylethernitrile, etc. Aromatic polyhydroxyether, polyacrylate, polymethacrylate, polyacrylonitrile, polyphenylene oxide, U.S. Pat.Nos. 3,986,212, 4,164,794, 4,202,
Organic substances such as those described in Nos. 055 and 4,351,069 (the contents of which are incorporated herein by reference). The amount of bone powder that can be added to the binder to form the osteogenic layer or film of the present invention can vary widely from about 5 to about 80% by weight, preferably from about 20 to about 60% by weight.

In addition to or instead of the above-mentioned optional substances in the bone powder, such substances can also be added to the binder.

Although the present invention is now specifically described for a hip endoprosthesis, the present invention can be practiced with any type of bone implant or alternative, such as those used for tooth or jaw facial reconstruction.

As shown in FIGS. 1-5, the femoral side member 10 of a known type of hip prosthesis may comprise a variety of bioengineering materials such as metals, ceramics, polymers, and composites thereof. Manufactured from Prosthesis includes head 11, neck 12, and femur 50
There is a stem 13 that serves to secure the implant within the medullary tubular section of the medulla. In one embodiment of the present invention, the binder 32 of the osteogenic layer 30 selected to be an enamel or enamel-like (similar) material is well known in the art, for example, a wet process, a dry process, It is applied to the surface of the stem portion 13 by using an enamelling method such as a method, an electrophoresis method, a flame spray method, and a plasma spray method. The binder may be applied as a single layer or as multiple layers, which may be of the same or different compositions. Bone powder particles 31 are added into the binder by injecting the bone particles by air blasting onto the still soft binder surface. The depth at which each of the bone particles 31 penetrates into the enamel binder is:
It will depend on the viscosity of the layer and the pressure of the particles 31 leaving the air blast against the binder surface. The thickness of the osteogenic layer 30 is not particularly important. About 1 to about 50 mils, preferably about 10 mils
Average thicknesses of from about to about 40 mils generally give good results. Of course, the bone particles 31 can be added into and / or onto the binder 32 by other methods, for example by pressing the particles into the enamelized layer by means of a mold containing the prosthetic workpiece.

When a synthetic organic polymer (polymer) as described above is selected for the binder component 32, one convenient method of applying an osteogenic membrane to a prosthesis is shown in FIGS. In this way, the plasticized body of the binder is first produced together with the demineralized bone which is substantially uniformly incorporated therein. Thus, for example, when the binder is a thermoplastic polyester, a certain amount of resin is plasticized into a paste using an appropriate solvent such as benzene, toluene, xylene, etc., and then the bone powder is uniformly added thereto. . Fluid material is excessively applied to the surface of the stem 13 and then the prosthesis is placed in the mold and the mold is closed, and the excess material is pushed out of the mold. Alternatively, the uncoated prosthesis is placed in one side 20 of the mold, the other side of the mold is fastened and the plastic osteogenic coating material is injected into space 21 in excess. . After the osteogenic layer 30 has been formed around the stem 13 as shown in FIG. 4, the prosthesis is removed from the mold and the plasticizing solvent is evaporated to produce a coated prosthesis as shown in FIG. , It is disinfected and stored aseptically.

In another method of applying the osteogenic membrane 30 to the fixation portion of the endoprosthesis 10, the binder is provided as a fine powder having an average particle size approximately equal to the demineralized bone powder particle size, and the bone powder is a binder powder. After the mixture is uniformly mixed to form a dry fluid powder mixture, the mixture is excessively placed in the space 21 of the mold 20.
Next, the powder mixture is heated to a temperature at which a self-supporting adherent film is formed, for example, a temperature sufficient to fuse the binder particles into one body, and then cooled to ambient temperature, whereby the coated prosthesis of the present invention is obtained. You can get it.

The osteogenic membrane 30 is obtained by first applying a solvent solution of a binder to the stem portion and evaporating one part of the solvent to give a sticky membrane, and then bringing the demineralized bone powder into contact with the binder and applying it to the binder. Thus, it can be applied to the surface of the stem 13. By repeating this method several times, a film having a predetermined thickness can be formed. The solvent is completely evaporated to complete the osteogenic membrane.

The thickness of the osteogenic membrane or layer is not particularly important. Average thicknesses of about 1 to about 50 mils, preferably about 10 to about 40 mils, generally provide satisfactory results.

If necessary, the surface of the prosthesis 13, such as the stem 13 to which the osteogenic membrane or layer is to be applied, may be pre-treated one or more times so that the membrane or layer adheres well thereto. For example, the surface of the prosthesis can be provided with an adhesion promoting pattern as described in US Pat. No. 4,778,469 or a rough surface morphology for promoting adhesion as described in US Pat. No. 4,159,358.

If necessary, the surface area of the osteogenic membrane 30 increases it, exposing the greater surface area of the bone particles to tissue fluids, cells, cell parts, etc., and / or surrounding any membrane parts as described above. Can be promoted to scatter. The increased surface area is obtained by membrane surface modification techniques using various known and common techniques, such as texturing, etching, embossing, sintering, introducing voids or holes into the layer.

The following examples illustrate the prosthetic implants and osteogenic membrane compositions of the present invention.

Example A. Preparation of demineralized cortical bone powder A fixed amount of ground cortical bone sieved to an average diameter of about 100 to about 300 microns was placed in a reactor and capped. After putting a 70% ethanol solution at a rate of 30m per gram of bone,
Stir for 1 hour (Volander's Journal of Bone and
Joint Surgery, Vol. 68-A, No. 8, (1986, October)), degreasing and disinfecting bone powder. After draining the ethanol, 50m of 0.6N hydrochloric acid solution per gram of bone was placed in the reactor (Volandera et al., Supra) and allowed to react for 3 hours. (Growackie, AATB Workshop, 11th Annual Meeting (1987)), hydrochloric acid was discharged, water for injection (WFI) was added, and the WFI was washed three times at 5 minute intervals. The WFI was drained and the bone was immersed in a 0.1 M sodium phosphate solution and repeated until the solution pH was between 6.8 and 7.4. WF
The I-washing method was repeated to obtain demineralized cortical bone powder, which could be used for the next application.

B. Application of demineralized cortical bone powder to the stem of hip endoprosthesis 20% by weight of powdered polybutylene terephthalate (PBT)
To 80% by weight m-cresol to form a solution of the PBT binder in m-cresol. The stem part of the hip joint artificial bone was immersed in a binder solution, and the solution was dried to be sticky, and bone powder was sprinkled on the surface of the binder to adhere. This procedure was repeated several times to form an osteogenic layer having an average thickness of about 2-3 mm containing about 40 to about 50% by weight of demineralized cortical bone powder on the stem surface of the artificial bone. After complete evaporation of the solvent in the drying cabinet, the coated prosthesis was disinfected and packaged in a known manner.

[Brief description of the drawings]

The same numbers in the attached drawings represent the same parts. FIG. 1 is a schematic illustration of a hip prosthesis having an osteoproliferation-inducing membrane according to the present invention wherein the prosthesis having the membrane is secured within the medullary tubular portion of the femur. FIG. 2 is an enlarged cross-sectional view of an osteoproliferative membrane as applied to the hip endoprosthesis of FIG. FIGS. 3-5 show side views of one method of applying the bone growth inducing membrane to the hip prosthesis of FIG.

────────────────────────────────────────────────── (5) References JP-A-1-15040 (JP, A) U.S. Pat. No. 4,2020,55 (US, A) U.S. Pat. No. 4,373,217 (US, A) U.S. Pat. 4,131,597 (US, A) U.S. Pat. (US, A) US Patent 4,472,840 (US, A) US Patent 4,778,469 (US, A) US Patent 4,159,358 (US, A) US Patent 3,987,499 (US, A) (58) Fields studied (Int. Cl. ⁷ , DB name) A61L 27/00 A61F 2/28 WPI (DIALOG)

Claims (15)

(57) [Claims] An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises A biocompatible (biocompatible) and biologically non-corrosive (non-bioerodable) binder applied to at least a portion of the surface of the device. A prosthetic bone device, wherein the binder is incorporated and the binder contains from 5 to 80% by weight of demineralized bone powder. 2. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is attached to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises The biocompatible and biologically non-corrosive binder is incorporated into a coating of a binder that is attached to at least a portion of the surface of the device, and the binder is 20-60
An artificial bone device, characterized in that it contains, by weight, demineralized bone powder. 3. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises Incorporated in a biocompatible and biologically non-corrosive binder coating that is attached to at least a portion of the surface of the device, wherein the binder is an enamel or enamel-like material An artificial bone instrument characterized by the following. 4. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises Incorporating a biocompatible and biologically non-corrosive binder applied to at least a portion of the surface of the device, wherein the binder is a synthetic organic polymer. A featured artificial bone instrument. 5. The polymer according to claim 1, wherein the polymer is porous high-density polyethylene, polypropylene, polysulfone, polyphenylene sulfide, polyacetal, thermoplastic polyester, polyamide, polyamideimide, thermoplastic polyimide, polyaryletherketone, polyarylethernitrile,
The artificial bone device according to claim 4, wherein the device is selected from the group consisting of aromatic polyhydroxyether, polyacrylate, polymethacrylate, polyacrylonitrile, and polyphenylene oxide. 6. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is attached to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises A biocompatible and biologically non-corrosive binder coating, which is attached to at least a portion of the surface of the device, wherein the binder comprises reinforcing fibers and particles. An artificial bone device comprising at least one additional component selected from the group consisting of: 7. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is attached to at least a portion of the surface of the artificial bone device, wherein the bone powder comprises an antiviral agent,
Antimicrobial agents, antibiotics, amino acids, peptides, vitamins, inorganic elements, DNA, hormones, endocrine tissue, synthesizers, enzymes, bone forming agents for polymer cells with parenchymal cells, pulse forming agents, polymeric drug carriers, collagen Lattes,
At least one selected from the group consisting of antigenic agents, cytoskeletal agents, biologically active ingredients, mesenchymal agents, bone digestive agents, antitumor agents, cell attractants, cell adhesion agents, immunosuppressants, nucleic acids, and permeability enhancers An artificial bone device comprising one additional component. 8. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises The biocompatible and biologically non-corrosive binder coating incorporated into at least a portion of the surface of the device is incorporated into the coating and the bone powder and / or binder is an antiviral agent. , Antibacterials, antibiotics, amino acids, peptides, vitamins, inorganic elements, DNA, hormones,
Endocrine tissue, synthesizers, enzymes, osteogenic agents of polymer cells with parenchymal cells, pulsating agents, polymerizable drug carriers, collagen lattices, antigenic agents, cytoskeletal agents, biologically active ingredients, mesenchymal agents, An artificial bone device comprising at least one additional component selected from the group consisting of a bone digestion agent, an antitumor agent, a cell inducer, a cell adhesion agent, an immunosuppressant, a nucleic acid, and a permeability enhancer. 9. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is attached to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises A biocompatible and biologically non-corrosive binder coating that is applied to at least a portion of the surface of the device is incorporated into the coating and has a thickness of 1 coating.
An artificial bone device characterized by being ~ 50 mils. 10. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises Incorporated in a coating of a biocompatible and non-bioerodible binder applied to at least a portion of the surface of the device, the coating having a thickness of 10-40.
An artificial bone device, which is a mill. 11. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, and the bone powder is applied to the surface of the artificial bone device. An artificial bone device wherein an adhesion promoting surface is provided on the device before the device is attached. 12. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises Applying the bone powder to the surface of the prosthetic bone device incorporated into a coating of a biocompatible and biologically non-corrosive binder that is adhered to at least a portion of the surface of the device. An artificial bone device wherein an adhesion promoting surface is provided on the device before the device is made to act. 13. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises Incorporating in a coating of a biocompatible and biologically non-corrosive binder attached to at least a portion of the surface of the device and improving the coating surface to increase its surface area An artificial bone instrument characterized by the following. 14. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is attached to at least a portion of the surface of the artificial bone device, wherein the device is orthopedic, dental or An artificial bone device, which is a jawbone facial prosthesis. 15. An artificial bone device wherein the amount of bone formation of the demineralized bone powder is adhered to at least a portion of the surface of the artificial bone device, wherein the demineralized bone powder comprises A biocompatible and biologically non-corrosive binder coating that is attached to at least a portion of the surface of the device, and wherein the device is an orthopedic, dental or jaw facial Bone prosthesis characterized by being a prosthesis for use.